Obmolova G, Ban C, Hsieh P, Yang W
Genetics and Biochemistry Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
Nature. 2000 Oct 12;407(6805):703-10. doi: 10.1038/35037509.
DNA mismatch repair is critical for increasing replication fidelity in organisms ranging from bacteria to humans. MutS protein, a member of the ABC ATPase superfamily, recognizes mispaired and unpaired bases in duplex DNA and initiates mismatch repair. Mutations in human MutS genes cause a predisposition to hereditary nonpolyposis colorectal cancer as well as sporadic tumours. Here we report the crystal structures of a MutS protein and a complex of MutS with a heteroduplex DNA containing an unpaired base. The structures reveal the general architecture of members of the MutS family, an induced-fit mechanism of recognition between four domains of a MutS dimer and a heteroduplex kinked at the mismatch, a composite ATPase active site composed of residues from both MutS subunits, and a transmitter region connecting the mismatch-binding and ATPase domains. The crystal structures also provide a molecular framework for understanding hereditary nonpolyposis colorectal cancer mutations and for postulating testable roles of MutS.
DNA错配修复对于提高从细菌到人类等各种生物体的复制保真度至关重要。MutS蛋白是ABC ATPase超家族的成员之一，可识别双链DNA中的错配和未配对碱基，并启动错配修复。人类MutS基因突变会导致遗传性非息肉病性结直肠癌以及散发性肿瘤的易感性。在此，我们报告了一种MutS蛋白以及MutS与含有未配对碱基的异源双链DNA复合物的晶体结构。这些结构揭示了MutS家族成员的总体结构、MutS二聚体的四个结构域与在错配处发生扭结的异源双链之间的诱导契合识别机制、由两个MutS亚基的残基组成的复合ATPase活性位点，以及连接错配结合结构域和ATPase结构域的传导区域。晶体结构还为理解遗传性非息肉病性结直肠癌突变以及推测MutS的可测试作用提供了分子框架。
